Receptor tyrosine kinases are mediators of extracellular signals through activation of downstream signaling pathways including ERK, AKT and/or STAT3 cascades to control cell growth, proliferation, survival and motility pathways. In particular, chromosome rearrangements, gene amplification, and point mutations in respective genes contribute to and/or result in abnormal and constitutive receptor tyrosine kinase activation which is, in turn, responsible for initiation and progression of many cancers including non-small cell lung cancer (NSCLC).
A receptor tyrosine kinase identified in cancers such as NSCLC is the anaplastic lymphoma kinase (ALK), wherein chromosome rearrangements of the ALK gene have been identified among which is as most common form the echinoderm microtubule-associated protein-like 4 (EML4)-ALK, i.e. comprising portions of the EML4 gene and the ALK gene, wherein several variants of EML4-ALK gene fusions have been identified. Furthermore, additional fusion partners besides EML4 have been identified and, additionally, ALK activating point mutations and presence of additional gene copies have been observed in cancers activating the signaling pathways downstream to ALK.
In the majority of cases, ALK chromosome rearrangements are non-overlapping with other gene abnormalities found in NSCLC (e.g. Gandhi, L. and Jänne, P. A., Clinical cancer research: an official journal of the American Association for Cancer Research, 2012, 18, 3737-3742). ALK oncogenic chromosome rearrangements, thus, define a unique molecular subset of NSCLC patients. Approximately 3-7% of NSCLCs harbor the ALK chromosome rearrangement (Takeuchi, K. et al., Nature medicine, 2012, 18, 378-381). The constitutive kinase activity associated with ALK chromosome rearrangements seems to play a particular role in cell growth, survival, and motility pathways in NSCLC (Davare, M. A. et al., Proceedings of the National Academy of Sciences of the United States of America, 2013, 110, 19519-19524, Sang, J. et al., Cancer discovery, 2013, 3, 430-443). ALK, thus, serves as a potent oncogenic “driver,” wherein cancers with chromosome rearrangements of ALK seem to be particular sensitive to ALK tyrosine kinase inhibition (Friboulet, L. et al., Cancer discovery, 2014, 4, 662-673).
The first generation ALK/ROS1/Met inhibitor crizotinib has demonstrated promising clinical benefit in NSCLC harboring chromosome rearrangements of ALK and has been approved by the Food and the Drug Administration for treatment of such NSCLC in 2011 (Gandhi, L. and Jänne, P. A., Clinical cancer research: an official journal of the American Association for Cancer Research, 2012, 18, 3737-3742). Although many patients with NSCLC harboring chromosome rearrangements of ALK derive substantial clinical benefit from crizotinib, durable responses to crizotinib therapy have been hampered because of acquired resistances as seen with most kinase inhibitors (Zou, H. Y. et al., Proceedings of the National Academy of Sciences of the United States of America, 2015, 112, 3493-3498, Lovly C. M., Pao, W., Science Translational Medicine, 2012, 4, 120). Accordingly, patients who responded to crizotinib will eventually experience disease progression despite continued treatment. Strategies to overcome said acquired resistance have not yet been established (Katayama, R. et al., Proceedings of the National Academy of Sciences of the United States of America, 2011, 108, 7535-7540).
Thus, further potent receptor tyrosine kinase inhibitors for cancer therapy have to be identified. Accordingly, there is a strong need for new compounds which are able to target receptor tyrosine kinases and sufficiently inhibit the kinase activity, in particular ALK kinase activity, which compounds can, thus, be used for cancer therapy, in particular for treatment of NSCLC.